This research aims to investigate phenotypic changes in intracellular metabolism and tumor micro-environment associated with the development of castrate resistant prostate cancer (CRPC) and its early response to therapy using a novel synergistic combination of hyperpolarized (HP) molecular imaging probes. Androgen deprivation therapy is the cornerstone of treatment for patients with recurrent or metastatic disease, but eventually patients stop responding to androgen deprivation and develop lethal CRPC. Advances in the understanding of CRPC have led to the development and clinical evaluation of a large number of new therapeutic approaches that effectively retard the growth of CRPC. However, current biochemical, clinical, and imaging biomarkers do not reliably predict the development of CPRC, or its subsequent response to therapy. HP MR is a revolutionary new MR molecular imaging technique providing 10,000-fold signal enhancement for HP 13C labeled probes, enabling rapid, noninvasive monitoring of multiple pathway-specific metabolic processes. Our strong preliminary data in the transgenic murine model of prostate cancer (TRAMP) have demonstrated the potential for using HP [1-13C] pyruvate to grade primary and metastatic prostate cancer. This project will investigate, for the first time, the utility of HP MRin early assessment of CPRC development and its subsequent response to a new 2nd-line anti-androgen therapy. In the TRAMP and human tissue slice models, we will further evaluate HP pyruvate metabolism, with HP probes of perfusion, interstitial pH and necrosis to advance our understanding of changes in tumor microenvironment with CPRC and therapeutic response. To provide the best indication of the individual value and synergistic role of the proposed HP probes, we will combine the ability of human prostate TSCs to better reflect the complex pathology, function, metabolism and androgen sensitivity in situ with information concerning the tumor micro-environment provided by the TRAMP model. In addition to these critical preclinical studies, this project will expand on the successful Phase 1 clinical trial of HP [1-13C] pyruvate i prostate cancer patients by obtaining the first HP MR data on response to anti- androgen therapy in CRPC patients. The long-term goal of this research is to provide companion MR imaging biomarkers that can be used to tailor treatment to individual patients with CRPC and to benefit future preclinical studies of new therapies and subsequent clinical trials. Therefore these landmark studies will greatly impact both the development of new therapeutics for CRPC as well as the new field of HP MR.

Public Health Relevance

This project aims to apply hyperpolarized 13C MR, a new molecular imaging technique, to address the important clinical need for new biomarkers to detect the early development of castrate resistant prostate cancer (CRPC) and its response to therapy in order to enhance the selection and effectiveness of new strategies that utilize anti-androgens in the treatment of patients with advanced disease.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-SBIB-Q (04))
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Zhang, Huiming
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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Aggarwal, Rahul; Vigneron, Daniel B; Kurhanewicz, John (2017) Hyperpolarized 1-[13C]-Pyruvate Magnetic Resonance Imaging Detects an Early Metabolic Response to Androgen Ablation Therapy in Prostate Cancer. Eur Urol 72:1028-1029
Chen, Hsin-Yu; Larson, Peder E Z; Bok, Robert A et al. (2017) Assessing Prostate Cancer Aggressiveness with Hyperpolarized Dual-Agent 3D Dynamic Imaging of Metabolism and Perfusion. Cancer Res 77:3207-3216
Milshteyn, Eugene; von Morze, Cornelius; Reed, Galen D et al. (2017) Development of high resolution 3D hyperpolarized carbon-13 MR molecular imaging techniques. Magn Reson Imaging 38:152-162
Sriram, Renuka; Van Criekinge, Mark; DeLos Santos, Justin et al. (2016) Non-invasive differentiation of benign renal tumors from clear cell renal cell carcinomas using clinically translatable hyperpolarized (13)C pyruvate magnetic resonance. Tomography 2:35-42
Korenchan, D E; Flavell, R R; Baligand, C et al. (2016) Dynamic nuclear polarization of biocompatible (13)C-enriched carbonates for in vivo pH imaging. Chem Commun (Camb) 52:3030-3
Koelsch, Bertram L; Sriram, Renuka; Keshari, Kayvan R et al. (2016) Separation of extra- and intracellular metabolites using hyperpolarized (13)C diffusion weighted MR. J Magn Reson 270:115-123
Keshari, Kayvan R; Wilson, David M; Van Criekinge, Mark et al. (2015) Metabolic response of prostate cancer to nicotinamide phophoribosyltransferase inhibition in a hyperpolarized MR/PET compatible bioreactor. Prostate 75:1601-9
Koelsch, Bertram L; Reed, Galen D; Keshari, Kayvan R et al. (2015) Rapid in vivo apparent diffusion coefficient mapping of hyperpolarized (13) C metabolites. Magn Reson Med 74:622-633
Leon Swisher, Christine; Koelsch, Bertram; Sukumar, Subramianam et al. (2015) Dynamic UltraFast 2D EXchange SpectroscopY (UF-EXSY) of hyperpolarized substrates. J Magn Reson 257:102-9
Sriram, Renuka; Van Criekinge, Mark; Hansen, Ailin et al. (2015) Real-time measurement of hyperpolarized lactate production and efflux as a biomarker of tumor aggressiveness in an MR compatible 3D cell culture bioreactor. NMR Biomed 28:1141-9

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